The number of patients suffering from arteriosclerosis is increasing due to population aging and an increase in the population with metabolic syndrome. Arteriosclerosis is an abnormality of arterial walls. In arteriosclerosis, a hyperglycemic state or hyperlipidemic state of blood causes degeneration of the vascular wall and, as a result, the vascular wall becomes weak or thickened, or calcification occurs to make the vascular wall hard and fragile. Although such blood vessel degeneration may occur at any site in the blood vessels in the body, peripheral blood vessels are especially remarkably affected by the degeneration.
Treatment of such a degenerated blood vessel is conventionally carried out by a minimally invasive endovascular treatment such as balloon dilation or stent placement using a catheter, or by surgery for replacement of the damaged blood vessel with a blood vessel of the patient him or herself or with an artificial blood vessel.
However, when an artificial blood vessel is used, the body recognizes the artificial blood vessel as a foreign substance, and blood clotting reaction proceeds on the blood-contacting surface of the artificial blood vessel to form a thrombus. A blood vessel in the body has an intima having vascular endothelial cells on its surface contacting with blood, and the intima plays a role in inhibiting formation of a thrombus. Also, in an indwelling artificial blood vessel, vascular endothelial cells cover the blood-contacting surface of the artificial blood vessel to form an intima. However, since the artificial blood vessel is recognized as a foreign substance until the intima is covered with the endothelial cells, means for preventing thrombus formation is required until formation of the intima. In particular, at a site where an artificial blood vessel having a small diameter is used, the blood flow is low so that deposition of thrombi easily occurs, and the blood vessel is likely to be clogged even with a small amount of thrombi. At present, the long-term performance of artificial blood vessels having small diameters is not good, and none of such artificial blood vessels is applicable for clinical use.
To solve these problems, development of artificial blood vessels has been conventionally carried out focusing on early intimal formation and early establishment of antithrombogenicity.
Examples of methods of promoting intimal formation include a method in which a growth factor or an inducer of cells is carried by the artificial blood vessel, and a method in which an artificial blood vessel containing, as its constitutional material, a fabric, knit, or non-woven fabric of a fiber such as a polyester fiber is used. In particular, it is known that, when an ultrafine fiber of less than 10 μm is included, the size of the ultrafine fiber or the size of the fiber gap is suitable for cell growth or cell infiltration (JP 1875991 B, JP 1870688 B and JP 1338011 B). It is also known that ultrafine fibers have effects to promote adhesion of platelets and prevent leakage of blood from the blood vessel wall when the fibers are indwelling (JP 4627978 B).
In a conventional method of imparting antithrombogenicity to an artificial blood vessel, heparin is carried by the artificial blood vessel. Since the fiber itself does not have a capacity to carry heparin, as methods of making the artificial blood vessel to carry a sufficient amount of heparin, a method in which a gel composed of a biodegradable polymer or gelatin containing heparin is filled into the gaps among the fibers (JP 3799626 B), and a method in which heparin is immobilized on the fiber surface by covalent bonds (Japanese Translated PCT Patent Application Laid-open No. 2009-545333) are known.
In addition, since heparin is ionically negatively charged, a method of carrying heparin on a surface of a base of a medical device by forming an ionic bond to a positively charged substance is known. By placing such a base in a body fluid or an aqueous solution, heparin is released over time. Since the antithrombogenicity can be controlled by controlling the release rate, combinations with various positively charged substances have been studied. A method in which an ion complex is formed with a quaternary ammonium compound and the ion complex is coated on a surface (JP 4273965 B); a method in which a polymer containing tertiary amino groups is coated, the tertiary amino groups are converted to quaternary ammonium groups, and heparin is bound thereto by ionic bonds (JP 3341503 B); and a method in which heparin is ionically bound to a surface of a base to which polyethyleneimine which is a polycation is bound (WO 00/13719 and JP 08-336587 A) are known.
However, when fiber gaps are filled such as in the artificial blood vessel described in JP 3799626 B, cellular infiltration is prevented to cause a delay in intimal formation and, furthermore, platelets adhere to gelatin and the like to rather promote thrombus formation, which is problematic. When heparin is immobilized on the fiber surface by covalent bonds such as in the artificial blood vessel described in Japanese Translated PCT Patent Application Laid-open No. 2009-545333, the amount of heparin that can be bound to the surface is limited because of the large molecular weight of heparin, and there is no long-term effect, which is problematic.
With the method described in JP 4273965 B in which an ion complex is formed with a quaternary ammonium low molecular compound, and the ion complex is dissolved in an organic solvent and coated on a surface of a base, a solvent which can dissolve the ion complex and which does not dissolve the base to be coated must be selected so that the solvent is limited. In addition, there is a problem in that since the hydrophilic moiety in the ion complex avoids the organic solvent to mutually coagulate during the coating solution is evaporated to cause a phase separation, the solution cannot be uniformly coated so that the release of heparin cannot be controlled. Further, since the quaternary ammonium low molecular compound and the surface of the base are not bound, the quaternary ammonium itself is also peeled off from the base, which is also a reason why the release of heparin cannot be controlled. With the method described in JP 3341503 B in which a polymer containing tertiary amino groups is coated, the amino groups are converted to quaternary ammonium, and heparin is bound ionically, a thick coating is required to carry a requisite amount of heparin. Therefore, when the polymer is coated on a base requiring a fine structure, the fine structure is buried so that the compatibility with cells is largely degraded. Further, since there is no bond with the surface of the base, when it is desired to firmly adhere the polymer, a solvent which also dissolves the base together with the polymer should be selected so that the solvent is limited. The solvent which dissolves the base used in artificial vessels such as polyester and polytetrafluoroethylene is very few. If the treatment described in JP 3341503 B is performed using a usual solvent, the polymer is readily peeled off, which is problematic with respect to safety when applied to humans.
Further, with the method described in WO 00/13719 and JP 08-336587 A in which heparin is ionically bound to a surface of a base to which polyethyleneimine which is a polycation is bound, since the primary to tertiary amino groups contained in the polyethyleneimine are weakly basic, part of the amino groups are not positively charged in an aqueous solution in which the heparin is ionically bound. As a result, the ionic interaction with heparin is weak so that the amount of the heparin which can be carried is limited.
Thus, even if the known technologies are used, conventional artificial blood vessels have failed in simultaneous achievement of cellular affinity and antithrombogenicity and, in particular, there is no artificial blood vessel having a small diameter that is available for long-term clinical use at present in the world.
In view of this, it could be helpful to provide an artificial blood vessel which promotes intimal formation after indwelling, and is capable of maintaining antithrombogenicity during intimal formation and maintaining its patency for a long time.